Linking myelin and Epstein-Barr virus specific immune responses in multiple sclerosis: insights from integrated public T cell receptor repertoires DOI Creative Commons
Sebastiaan Valkiers,

Amber Dams,

Maria Kuznetsova

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 25, 2024

Abstract The autoimmune responses in multiple sclerosis (MS), particularly those mediated by T cells targeting CNS-derived antigens, are broadly recognized. However, the defining triggers underlying these remain poorly understood. Epstein-Barr virus (EBV) infection has emerged as a primary risk factor for MS, suggesting potential role molecular mimicry which EBV-specific immune cross-react with myelin antigens. In this study, we analyzed cell receptor (TCR) repertoires of MS patients (n = 129) and controls 94) from public datasets, to explore relationship between myelin-specific responses. Our analysis identified clusters TCRs that were significantly depleted among patients, many associated cytomegalovirus (CMV). By generating library myelin-reactive stimulated peripheral blood mononuclear (PBMCs) obtained mapping sequences TCR repertoire database, also uncovered lower frequency samples compared datasets. addition, epitope-specificity prediction revealed broader response EBV-, but not CMV-derived epitopes. Collectively, findings underscore complex chronic viral infections MS. Particularly, they suggest contribute dysregulation system potentially through mechanisms mimicry. While EBV-derived epitopes both disease, further research is needed clarify nature relationship. These observations may independently or interact pathogenesis.

Language: Английский

Can we predict T cell specificity with digital biology and machine learning? DOI Open Access
D. R. Hudson, Ricardo A. Fernandes, Mark Basham

et al.

Nature reviews. Immunology, Journal Year: 2023, Volume and Issue: 23(8), P. 511 - 521

Published: Feb. 8, 2023

Language: Английский

Citations

120
Human SARS-CoV-2 challenge uncovers local and systemic response dynamics DOI Creative Commons
Rik G.H. Lindeboom, Kaylee B. Worlock, Lisa M. Dratva

et al.

Nature, Journal Year: 2024, Volume and Issue: 631(8019), P. 189 - 198

Published: June 19, 2024

The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the dynamics early cellular responses to this disease remains limited

Language: Английский

Citations

53
Contrastive learning of T cell receptor representations DOI Creative Commons
Yuta Nagano,

Andrew G. T. Pyo,

Martina Milighetti

et al.

Cell Systems, Journal Year: 2025, Volume and Issue: unknown, P. 101165 - 101165

Published: Jan. 1, 2025

Language: Английский

Citations

1
A unified cross-attention model for predicting antigen binding specificity to both HLA and TCR molecules DOI

Chenpeng Yu,

Xing Fang,

Shiye Tian

et al.

Nature Machine Intelligence, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Language: Английский

Citations

1
Multi-modal generative modeling for joint analysis of single-cell T cell receptor and gene expression data DOI Creative Commons
Felix Drost, 洋一 岸, Irene Bonafonte-Pardàs

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 3, 2024

Recent advances in single-cell immune profiling have enabled the simultaneous measurement of transcriptome and T cell receptor (TCR) sequences, offering great potential for studying responses at cellular level. However, integrating these diverse modalities across datasets is challenging due to their unique data characteristics technical variations. Here, address this, we develop multimodal generative model mvTCR fuse modality-specific information TCR into a shared representation. Our analysis demonstrates added value over unimodal approaches capture antigen specificity. Notably, use distinguish subpopulations binding SARS-CoV-2 antigens from bystander cells. Furthermore, when combined with reference mapping approaches, can map newly generated extensive references, facilitating knowledge transfer. In summary, envision enable scalable advance our understanding responses.

Language: Английский

Citations

8
A comparison of clustering models for inference of T cell receptor antigen specificity DOI Creative Commons
D. R. Hudson, Alexander L. R. Lubbock, Mark Basham

et al.

ImmunoInformatics, Journal Year: 2024, Volume and Issue: 13, P. 100033 - 100033

Published: Jan. 29, 2024

The vast potential sequence diversity of TCRs and their ligands has presented an historic barrier to computational prediction TCR epitope specificity, a holy grail quantitative immunology. One common approach is cluster sequences together, on the assumption that similar receptors bind epitopes. Here, we provide first independent evaluation widely used clustering algorithms for specificity inference, observing some variability in predictive performance between models, marked differences scalability. Despite these differences, find different produce clusters with high degrees similarity recognising same epitope. Our analysis strengthens case use models identify signals from large repertoires, whilst highlighting scope improvement complex over simple comparators.

Language: Английский

Citations

7
The Observed T cell receptor Space database enables paired-chain repertoire mining, coherence analysis and language modelling DOI Creative Commons
Matthew I. J. Raybould, Alexander Greenshields‐Watson,

Parth Agarwal

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 21, 2024

T cell activation is governed through receptors (TCRs), heterodimers of two sequence-variable chains (often an alpha [ α ] and beta β chain) that recognise linear antigen fragments presented on the surfaces. Early sequencing technologies limited study immune repertoire TCRs to unpaired transcripts, leading extensive analysis -chain data alone as its greater sequence diversity suggested it should dominate recognition. Over time, structural has revealed both contribute binding most antigens highthroughput single-cell handling have been increasingly applied obtain samples complete TCR variable region sequences from repertoires. Despite this, there currently no repository dedicated curation publicly available paired data. We addressed this gap by creating Observed receptor Space (OTS) database, a source consistently processed annotated, full-length, paired-chain 50 studies at least 75 individuals. Currently, OTS contains 5.35M redundant (1.63M nonredundant) predominantly human and, based recent availability trends, will grow rapidly. perform initial OTS, identification pairing biases, public TCRs, distinct chain coherence patterns relative antibodies. also harness build language model, providing embedding representations method for residue in-filling conditional partner chain. be updated maintained central community resource freely downloadable web application https://opig.stats.ox.ac.uk/webapps/ots .

Language: Английский

Citations

7
Human SARS-CoV-2 challenge resolves local and systemic response dynamics DOI Creative Commons
Rik G.H. Lindeboom, Kaylee B. Worlock, Lisa M. Dratva

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 25, 2023

Abstract The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the cellular disease dynamics remains limited. In unique human challenge study we used single cell genomics nasopharyngeal swabs and blood to temporally resolve abortive, transient sustained infections in 16 seronegative individuals challenged with preAlpha-SARS-CoV-2. Our analyses revealed rapid changes type proportions dozens highly dynamic response states epithelial immune cells associated specific timepoints or infection status. We observed that interferon precedes nasopharynx, infiltration occurred early but later infection, thus correlated preventing infection. Ciliated showed acute phase, upregulated MHC class II while infected, were most permissive for viral replication, whilst nasal T macrophages infected non-productively. 54 states, including acutely activated clonally expanded carrying convergent SARS-CoV-2 motifs. novel computational pipeline (Cell2TCR) identifies antigen-responding clonotype groups motifs any dataset. Together, show detailed time series data ( covid19cellatlas.org ) can serve as a “Rosetta stone” responses, reveals responses protection from

Language: Английский

Citations

13
Combining mutation and recombination statistics to infer clonal families in antibody repertoires DOI Creative Commons
Natanael Spisak, Gabriel Athènes, Thomas Dupic

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Aug. 9, 2024

B-cell repertoires are characterized by a diverse set of receptors distinct specificities generated through two processes somatic diversification: V(D)J recombination and hypermutations. clonal families stem from the same event, but differ in their Clonal identification is key to understanding repertoire function, evolution, dynamics. We present HILARy (high-precision inference lineages antibody repertoires), an efficient, fast, precise method identify single- or paired-chain sequencing datasets. combines probabilistic models that capture receptor generation selection statistics with adapted clustering methods achieve consistently high accuracy. It automatically leverages phylogenetic signal shared mutations difficult subsets. Exploiting sensitivity method, we find evolutionary properties such as site frequency spectrum d N / S ratio do not depend on junction length. also broad range pressures spanning orders magnitude.

Language: Английский

Citations

5
Defining and Studying B Cell Receptor and TCR Interactions DOI
C. Garrett Rappazzo, Monica L. Fernández‐Quintero, Andreas Mayer

et al.

The Journal of Immunology, Journal Year: 2023, Volume and Issue: 211(3), P. 311 - 322

Published: July 17, 2023

Abstract BCRs (Abs) and TCRs (or adaptive immune receptors [AIRs]) are the means by which system recognizes foreign self-antigens, playing an integral part in host defense, as well emergence of autoimmunity. Importantly, interaction between AIRs their cognate Ags defies a simple key-in-lock paradigm is instead complex many-to-many mapping individual’s massively diverse AIR repertoire, similarly antigenic space. Understanding how immunity balances specificity with epitopic coverage key challenge for field, terms such broad specificity, cross-reactivity, polyreactivity remain ill-defined used inconsistently. In this Immunology Notes Resources article, group experimental, structural, computational immunologists define commonly associated binding, describe methodologies to study these binding modes, highlight implications different modes therapeutic design.

Language: Английский

Citations

12